Tobey John MacDonald, M.D., received fellowship training in pediatric hematology/oncology at Children's Hospital Los Angeles from 1994-1998 and is now Assistant Professor of Pediatrics, Clinical Director of Neuro-Oncology, and Member of the Children's Research Institute of the Children's National Medical Center (CNMC) in Washington, DC. His past training and publications have centered on the role of serine proteases and integrins in the growth, invasion and angiogenesis of central nervous system tumors. Using in vitro and in vivo experimental models, he has recently demonstrated that alpha-v integrins function to promote medulloblastoma growth. To pursue this line of research, and to guarantee protected time toward the development of an independent research career, Dr. MacDonald was granted an Avery Scholarship Award by the Children's Research Institute in 1999. With this support, Dr. MacDonald developed an antisense strategy to reduce the level of alpha-v integrin expression by medulloblastoma cells so that the precise function of these molecules in medulloblastoma could be further tested. With the support of a Mentored Clinical Scientist Development Award, Dr. MacDonald plans to use this strategy to identify the mechanisms by which alpha-v integrins promote the growth and survival of medulloblastoma cells. The hypothesis is that alpha-v integrins cooperate with growth factor receptors within integrin-ligand complexes to potentiate signal transduction. The specific aims of the project are to determine the effect of medulloblastoma alpha-v integrin reduction on: 1) growth factor and receptor expression, 2) growth factor-mediated proliferation, survival and initial activation of 2 central growth-promoting signal transduction pathways, and 3) experimental tumor growth and angiogenesis. Integrin-mediated signal transduction is a new area of pursuit for Dr. MacDonald. With co-mentorship by Dr. Mary Ann Stepp, a leading expert in integrin signaling and biology, Dr. MacDonald is expected to obtain the technical skills and guidance necessary to carry out this investigation. Through the sponsorship of Dr. Stephan Ladisch, Scientific Director of the Children's Research Institute, and the resources and formal training provided by the Career Development Program established at CNMC, the short-range scientific goals of this project can be accomplished. With additional co-mentorship by Dr. Roger Packer, a renowned clinical neuro- o n cologist, Dr. MacDonald hopes to develop an independent career in translational research within 3-5 years. The long-range goal of this work is to broaden our understanding of medulloblastoma growth, so that novel biologic therapies may be developed into new treatments for medulloblastoma, the most common malignant brain tumor in children.